Magnetic nanoparticles such as those made of Fe3O4, FePt, Co, or Mn-doped Fe3O4 exhibit unique size- and composition-dependent physical properties that are not observed at the molecular scale or shared by their bulk parent materials. See references 1-7. This has generated a great deal of interest to integrate them into electronic devices and as contrast enhancement agents for Magnetic Resonance Imaging (MRI). See references 1-4, 6, and 7. Other potential applications in biology include use as magnetic carriers for drug delivery platforms, biosensors, hyperthermia and bioseparation. See references 8-13. Magnetic NPs as contrast enhancing agents for MR imaging and sensing have generated considerable attention and much work in the past decade. This has motivated researchers to develop new synthetic schemes to prepare large quantities of high quality magnetic nanoparticles and to conceive new surface-functionalization strategies for post growth manipulation and processing.
An effective integration of magnetic NPs into biology requires the availability of NPs with homogenous composition, reduced size distribution, high coercivity, and the ability to interface them with biological systems. Thus far, the most successful route to prepare high quality iron oxide (IO) nanoparticles (NP) with controllable size and high crystallinity has relied on the thermal decomposition of metal precursors (such as iron oleate, iron pentacarbonyl and iron acetylacetonate) in hot surfactant solution. See references 14-18. However, nanocrystals synthesized via thermolysis of organometallic precursors are capped with hydrophobic ligands, which make them dispersible only in organic solvents. Therefore, any use in bio-inspired investigations requires additional chemical manipulation and post growth surface modification to render the magnetic NPs colloidally stable in buffer media and biocompatible. See references 4 and 19-22.
Two main strategies have emerged as reliable approaches for interfacing these materials with biological systems. One uses amphiphilic polymers (e.g., copolymers and phospholipids) to encapsulate the as-prepared hydrophobic nanoparticles within micelle-like structures; it relies on the interdigitation (an entropy-driven process) between the hydrophobic segments of the polymers and the native cap. Such strategy has been employed by several groups to prepare various water-soluble NPs and to couple them to biomolecules. See references 23-30. Encapsulation preserves the native organic cap, which may be beneficial as this can better preserve the physical properties of the native materials (e.g., optical or magnetic), but tends to significantly increase the hydrodynamic size of the nanoparticles and may yield more than one nanocrystal per micelle. See references 23 and 30. This will limit their use in applications requiring small size probes. The other strategy relies on the removal of the hydrophobic shell and replacing it with bifunctional ligands that present anchoring groups and hydrophilic moieties: ligand exchange. These anchors interact with the metal surface via Lewis-base type coordination. This route should, in principle, provide compact NPs and better colloidal stability in physiological conditions, if the ligands present strong anchoring groups to NP surfaces. For Fe3O4 and γ-Fe2O3 magnetic nanocrystals, dopamine has been reported to exhibit specific affinity to the NP surface, a feature attributed to the improved orbital overlap of five-membered catechol ring and reduced steric effects. See references 9 and 31.
Several monodentate dopamine-modified ligands, such as dopamine-PEG-carboxy/amine and zwitterionic dopamine sulfonate have been used for preparing colloidal dispersions of iron oxide NPs in water media, due to ease of implementation. See references 32 through 34. Similarly, ligation with monodentate moieties has been applied to transfer a wide range of inorganic nanocrystals (e.g., metal NPs and quantum dots) to buffer media. However, the binding affinity of such monodentate ligands to the NP surface is weak, and this can result in irreversible ligand desorption from the NP surfaces due to the dynamic nature of coordination interactions. This can negatively affect the NP stability in biological media, in particular at low concentrations. Furthermore, ligands with weak affinity can be easily displaced by biomolecules bearing amine and carboxylic functional groups, which will eventually promote NP aggregation, making this strategy ineffective. See reference 22. Such problems should be overcome by developing multi-coordinating ligands, which improve the NP colloidal stability in biological media by enhancing the ligand affinity to the NP surfaces. See references 35 through 40. Our group has previously reported the design of multi-dopamine modified ligand consisting of a short poly(acrylic acid) (PAA) backbone laterally appended with a few catechol groups and several poly(ethylene glycol) (PEG) moieties via N,N′-dicyclohexylcarbodiimide (DCC) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) condensation. See reference 40. The resulting aqueous iron oxide (IO) nanoparticles (NP) were stable for one month in high acidic/basic conditions and at least 6 months in DI water. However, the use of polyacrylic acid (PAA) precursor for modification, where close proximity of the COOH groups along the backbone combined with the need to use DCC/EDC reagents, produced ligands with lower numbers of metal-coordinating groups (˜6 dopamines per PAA chain); the PAA-based ligands also required thorough post-synthesis purification.
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